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Initially, NF-\u03baB signaling was identified as a pivotal pathway in mediating inflammatory responses. However, with extensive and in-depth investigations, researchers have discovered that its role can be expanded to a variety of signaling mechanisms, biological processes, human diseases, and treatment options. In this review, we first scrutinize the research process of NF-\u03baB signaling, and summarize the composition, activation, and regulatory mechanism of NF-\u03baB signaling. We investigate the interaction of NF-\u03baB signaling with other important pathways, including PI3K\/AKT, MAPK, JAK-STAT, TGF-\u03b2, Wnt, Notch, Hedgehog, and TLR signaling. The physiological and pathological states of NF-\u03baB signaling, as well as its intricate involvement in inflammation, immune regulation, and tumor microenvironment, are also explicated. Additionally, we illustrate how NF-\u03baB signaling is involved in a variety of human diseases, including cancers, inflammatory and autoimmune diseases, cardiovascular diseases, metabolic diseases, neurological diseases, and COVID-19. Further, we discuss the therapeutic approaches targeting NF-\u03baB signaling, including IKK inhibitors, monoclonal antibodies, proteasome inhibitors, nuclear translocation inhibitors, DNA binding inhibitors, TKIs, non-coding RNAs, immunotherapy, and CAR-T. Finally, we provide an outlook for research in the field of NF-\u03baB signaling. We hope to present a stereoscopic, comprehensive NF-\u03baB signaling that will inform future research and clinical practice.<\/jats:p>","DOI":"10.1038\/s41392-024-01757-9","type":"journal-article","created":{"date-parts":[[2024,3,3]],"date-time":"2024-03-03T19:03:43Z","timestamp":1709492623000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2189,"title":["NF-\u03baB in biology and targeted therapy: new insights and translational implications"],"prefix":"10.1038","volume":"9","author":[{"given":"Qing","family":"Guo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizi","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomin","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxi","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teng","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,4]]},"reference":[{"key":"1757_CR1","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1016\/0092-8674(86)90346-6","volume":"46","author":"R Sen","year":"1986","unstructured":"Sen, R. & Baltimore, D. 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